The FDA has approved the combination of the BRAF inhibitor Braftovi (encorafenib) and the MEK inhibitor Mektovi (binimetinib) for the treatment of patients with BRAF-mutant unresectable or metastatic melanoma, as detected by an FDA-approved test.

The approval is based on the phase 3 COLUMBUS trial, in which at a median follow-up of 36.8 months, combining Braftovi at 450 mg daily and Mektovi at 45 mg twice daily (COMBO450) reduced the risk of death by 39 percent versus Zelboraf (vemurafenib) monotherapy. The median overall survival (OS) was 33.6 months versus 16.9 months, respectively.

The two-year OS rates were 58 percent versus 43 percent and the three-year OS rates were 47 percent versus 32 percent with COMBO450 versus single-agent Zelboraf, respectively. The OS benefit with the combination was maintained across all subgroups including those defined by sex, age, BRAF status, LDH level, tumor stage and number of organs involved at baseline.

The COLUMBUS findings also showed a trend toward an OS benefit with ENCO450 versus single-agent Braftovi at 300 mg daily (ENCO300). The 33.6-month median OS with ENCO450 compared favorably with the 23.5 month median OS with ENCO300. The HR ratio of 0.81 for the comparison was not statistically significant at the time of the data presentation.

Comparing the two BRAF inhibitors as single agents, there was statistically significant OS benefit with ENCO300 versus single-agent Zelboraf. The median OS was 23.5 months versus 16.9 months in the two arms, respectively.

The full COLUMBUS trial included 921 patients with BRAF V600-mutant melanoma, with 577 in part 1 and 344 in part 2. In part 1, patients were randomized in a 1 to 1 to 1 ratio to receive COMBO450 (192 patients), ENCO300 (194 patients) or Zelboraf at 960 mg twice daily (191 patients). In part 2, patients were randomized 3 to 1 to Braftovi at 300 mg daily plus Mektovi at 45 mg twice daily (258 patients) or ENCO300 (86 patients).

The OS data above are from the latest study update for the 577-patient part 1 of the trial that were reported at the 2018 ASCO Annual Meeting. The part 1 ASCO update also showed that at a median follow-up of 32.1 months, the median progression-free survival (PFS) was 14.9 months with COMBO450 versus 7.3 months with single-agent Zelboraf. The two-year PFS rates were 37 percent versus 20 percent and the three-year PFS rates were 28 percent versus 13 percent with COMBO450 versus single-agent Zelboraf, respectively.

The COMBO450 median PFS also compared favorably with the 9.6-month median PFS with ENCO300. The median PFS with ENCO300 was improved over the median PFS with Zelboraf monotherapy.

Patient characteristics for part 1 of the trial were well balanced across treatment arms. The median age of patients ranged from 54 to 57 years and the majority had an ECOG performance status of 0 (~72 percent). LDH levels were greater than or equal to the upper limit of normal for about one-third of patients, and about two-thirds of patients had IVM1c tumor stage at study entry. One percent of patients in each arm had prior Yervoy (ipilimumab) in the adjuvant or neoadjuvant setting. In the advanced/metastatic settings 3 percent, 5 percent, and 3 percent of patients had received Yervoy in the COMBO450, ENCO300, and Zelboraf arms, respectively.

At the time of the data cutoff for the ASCO presentation, 78 percent of patients in the COMBO450 arm had discontinued treatment, along with 87 percent of patients in the ENCO300 arm and 91 percent of patients in the Zelboraf arm. The primary reason for discontinuing treatment was progressive disease at 52 percent, 52 percent and 57 percent, in the 3 arms, respectively. Adverse events (AEs) were the secondary reason for discontinuation, at 10 percent, 13 percent, and 13 percent, respectively.

The median duration of treatment exposure was 51 weeks with COMBO450, compared with 31 weeks with ENCO300 and 26 weeks with Zelboraf monotherapy. Grade 3/4 AEs occurred in 64 percent, 67 percent, and 66 percent of the 3 arms, respectively. On-study deaths or death within 30 days of stopping study treatment occurred in 12 percent, 8 percent, and 11 percent of the 3 arms, respectively.